Abstract: FR-PO185

Renal Hemodynamic Effects of sGC Activation versus ACE Inhibition in Conscious Rats

Session Information

Category: Hypertension

  • 1103 Vascular Biology and Dysfunction

Authors

  • Griffin, Karen A., Loyola University Medical Center Hines VA Hospital, Maywood, Illinois, United States
  • Williamson, Geoffrey A., Illinois Institute of Technology, Chicago, Alabama, United States
  • Polichnowski, Aaron J., East Tennessee State University, Johnson City, Tennessee, United States
  • Sethupathi, Perriannan, Loyola University Medical Center, Maywood, Illinois, United States
  • Benardeau, Agnes M, Bayer AG, Wuppertal, Germany
  • Eitner, Frank, Bayer AG, Wuppertal, Germany
  • Bidani, Anil K., Loyola University Med Ctr and Hines VA Hospital, Maywood, Illinois, United States
Background

Substantial evidence indicates that endothelial dysfunction and/or NO loss accelerates the progression of diabetic and non-diabetic chronic kidney disease (CKD). Therefore, soluble guanylate cyclase (sGC) modulators are being developed as potential novel therapeutic interventions in CKD, but only limited data are available as to their renal hemodynamic effects, particularly in the unanesthetized state.

Methods

Conscious chronically instrumented normal Sprague-Dawley rats (Charles River & Envigo) underwent repeated simultaneous 1-2 hr BP (radiotelemetry) and RBF (Transonic) recordings over 3 wks (2-4 x wk) while they were sequentially receiving: vehicle only by gavage (5 ml/kg), a low and a high dose of either the sGC activator (Bay-543) or enalapril (4 d/wk with a 3d washout). Effects on mean arterial pressure (MAP), RBF and the autoregulatory AR ability to buffer spontaneous BP fluctuations were assessed using a methodology recently developed in our lab (AR indices are calculated for ~500 adjacent pairs of short segments of 2.5 sec length/rat, which exhibit a difference in MAP of at least 5mmHg, SSARI). GFR was additionally measured during each wk using chronic FITC inulin infusion by osmotic pumps, and 24 hr urine collections. The data for both colonies of SD rats are combined as the results were similar.

Results

Table (mean + SEM)

GFR was not significantly or consistently altered by either agent. Thus, while both agents reduced BP comparably, significantly greater dose dependent renal vasodilation was observed with the sGC activator, while a more modest RBF increase was only seen with the higher dose of enalapril. Surprisingly, AR buffering of spontaneous BP fluctuations was moderately improved by the sGC activator but not enalapril.

Conclusion

Collectively, the BP and renal hemodynamic effects of sGC activation suggest that sGC modulators may have significant therapeutic utility in CKD states, meriting additional and more direct investigations in CKD models.

 sGC activator, BAY-543 (n=24)Enalapril (n=14)
 Vehicle3 mg/kg10 mg/kg (n=18)Vehicle20 mg/kg50 mg/kg (n=13)
MAP (mmHg)114.3±2.1110.2±1.8*104.0±2.8*#116.6±2.8107.7±2.9*104.8±2.5*#
RBF ml/min7.1±0.38.0±0.4*9.2±0.6*#8.4±0.38.3±0.49.2±0.4*
SSARI0.48±0.040.32±0.04*0.29±0.03*0.53±0.060.63±0.060.61±0.06

* p<0.05 minimum vs. vehicle; # p<0.05 minimum vs lower dose (repeated measures analysis of variance)

Funding

  • Commercial Support